Utilizing environmental information to predict future positive and negative outcomes is a behavioral adaptation that is essential for survival. While this process is required for the control of natural motivated behavioral responding to obtain rewards, the neural circuits that encode cue-reward associations are thought to be dysfunctional in neuropsychiatric disorders such as addiction. Therefore, it is essential that further research is conducted to delineate the neural mechanism that underlie responses to reward-predictive cues in an effort to uncover specific neural circuit elements that mediate this phenomena. Signaling by midbrain dopamine neurons is thought to play an important role in controlling the formation and expression of cue-induced reward seeking. In this proposal, we aim to study neural circuit elements within the ventral midbrain that may be important for activating or inhibiting dopaminergic function and therefore influence the acquisition and expression of cue-reward associations. To accomplish this, we will take a multifaceted approach. We will perform in vitro slice electrophysiological experiments to characterize the functional connectivity between specific excitatory inputs to dopaminergic and GABAergic neurons within the midbrain. In addition, we will use in vivo optogenetic stimulation/inhibition experiments to establish or refute causal relationships between genetically and anatomically defined neural circuit elements in the midbrain and the release of dopamine in the nucleus accumbens to reward-predictive cues. The information gained from these studies may greatly advance our understanding of the neural circuits that encode cue-reward associations. PUBLIC HEALTH RELEVANCE: Psychiatric and neurological diseases and disorders have a tremendous impact on society. Despite improved diagnosis and treatment, further advancement is significantly hindered by a lack of understanding how alterations in neural circuit function leads to the development and expression of disease states. The research directions outlined in this proposal will characterize the function of key neural circuits that are involved in psychiatric disease such as substance abuse disorders. We aim to study these neural circuit elements in order to identify potentially novel therapeutic targets for the treatment neuropsychiatric disorders.